Cells and mechanisms involved in natural cell mediated resistance against the yeast-like organism, Cryptococcus neoformans are not well defined. There are three different cell populations in normal unstimulated animals which have the potential to clear cryptococci from tissues. These are polymorphonuclear leukocytes (PMNL), macrophages, and natural killer (NK) cells. Over the past three years, we have studied the effects of natural effector cells on C. neoformans both in vivo and in vitro. From these studies, it is clear that normal mice have cells which have anti-Cryptococcus activity and by numerous criteria, have characteristics matching NK cells. Although NK cells are not capable of sterilizing a culture of 10/3 cryptococci nor totally eliminating C. neoformans from mice infected with 10/4 organisms, they do significantly reduce the numbers of cryptococci in both cases. These findings suggest that NK cells participate along with PMNL and macrophages in initial clearance of cryptococci from host tisuses. NK cells affect C. neoformans by a nonphagocytic mechanism which includes first binding of the NK cells to the organism then later inhibiting the growth of the cryptococci. The lytic effects of cytotoxic T lymphocytes (CTL) and NK cells against appropriate tissue targets appear to be the result of effector cell exocytosis of granules containing cytolytic components. We are proposing that a similar mechanism may be operating in NK cell mediated inhibition of cryptococci growth. However, our earlier studies have shown that the kinetics of NK cell binding to cryptococci and inhibition of cryptococci growth are much slower than with tumor cell targets. This suggests there may be differences in the way the NK cells respond to binding of cryptococci targets versus tumor cell targets and in the active components or the means by which active components of NK cells affect the yeast target. We now propose investigations to gain a basic understanding of interactions of NK cells with cryptococci, a target which is substantially different from previously studied NK targets. To do this we will determine the sequence of steps leading to inhibition of cryptococci growth, study the changes occurring in the effector and target cells after binding using light and electron microscopy techniques, and asses what specific component(s) of the NK cells is responsible for the anti-Cryptococcus activity. These studies should provide new and significant information on the mechanisms of natural cell mediated resistance in cryptococcosis.